Download vulva and vagina

FEMALE GENITALIA I
VULVA , VAGINA and CERVIX UTERI
Student-Learning Objectives:
At the end of this lecture the student should be able to:
 Classify the main diseases affecting vulva, vagina and cervix.
 Define vulvar and cervical intraepithelial neoplasia.
 Discuss vulvar and cervical intraepithelial neoplasia in terms of aetiology, epidemiology,
pathological features and implications.
 Describe the clinico-pathological features of invasive squamous cell carcinoma of the
vulva.
 Describe the clinico-pathological features of invasive cervical carcinoma
(including the staging of the disease)
VULVA
Vulval diseases may be discussed under the following headings:
 Cysts
 Infectious/Inflammatory conditions
 Non-neoplastic epithelial disorders (Chronic vulvar dystrophies)
 Neoplasms
CYSTS
Most vulval cysts are of little pathological significance.
They may be of epidermal or dermal origin. Some are developmental and others are acquired.
Cysts and/or abscesses of the Bartholin’s glands are the most common clinically important cystic
lesions of the vulva.
Bartholin’s cysts form secondary to duct obstruction often due to chronic inflammation and
scarring. The abscess is often a sequel of gonorrheal infection.
Clinical picture of Bartholins cyst
INFECTIOUS/INFLAMMATORY CONDITIONS
Some of these are sexually transmitted infections (STIs), and include granuloma inguinale,
lymphogranuloma venereum, syphilis, herpes simplex and human papillomavirus infection.
Non-STIs include Crohn's disease and miscellaneous bacterial and fungal infections.
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Granuloma Inguinale (GI)
This is caused by a gram-negative coccobacillus (Calymmatobacterium granulomatis) and is
represented by lesions, which vary from painless papules to ulcerating, necrotic, granulating lesions.
The inflammatory infiltrate is rich in macrophages and plasma cells. On special staining with
Giemsa or silver stains, the organisms - Donovan bodies - may be seen extracellularly and within
macrophages.
Lymphogranuloma Venereum (LGV)
This is caused by Chlamydia trachomatis and is characterized by inguinal lymph node
inflammation and enlargement (buboes). The disease has three phases giving the following lesions:
a) Small ulcers (usually painless) - located at the site of the venereal contact
b) Bartholin gland inflammation +/- abscess formation
c) Scarring with fistulae/strictures of urethra, vagina and/or rectum (in chronic cases).
Scarring may lead to lymphatic obstruction with chronic lymphedema, which can cause
elephantiasis of the vulva.
The histological picture is nonspecific and the organisms are not seen histologically.
Clincal picture of LGV1
Clinical picture of LGV2
Syphilis
 Primary - characterized by the chancre, a painless papule that usually ulcerates. Chancre
 Secondary - features include a maculo-papular rash and condylomata lata. The latter are plaquelike lesions represented by epithelial proliferation and a plasma cell rich mononuclear
inflammatory infiltrate. The causative organism, Treponema pallidum, may be seen in the
lesions when stained with the appropriate silver stain. Secondary syphilis, condylomata lata
 Tertiary syphilis rarely affects the vulva.
Herpes Simplex Virus (HSV) Infection
This is caused by herpes simplex virus (usually type 2) that results in the formation of painful
vesicles. There is secondary ulceration with infection.
Histological examination shows typical cytopathic effects of the virus that include nuclear
homogenization (ground glass appearance) and multinucleation with intranuclear inclusion bodies.
Herpes vulvitis
Human papillomavirus (HPV) Infection
The importance of this infection lies primarily in the association between HPVs and neoplasia of
the vulva and cervix uteri – discussed later.
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NEOPLASMS
Benign
These comprise a miscellaneous group and include benign skin adnexal tumours, haemangiomas,
lipomas etc.
Condylomata acuminata (singular - condyloma acuminatum) are anogenital warts – benign
sexually transmitted neoplasms (papillomas) caused by HPV. They may occur singly but are
usually multiple, and are verrucous, papillomatous lesions comprising stratified squamous
epithelium on vascular connective tissue stalks.
The squamous epithelium shows the typical cytopathic features of HPV infection – koilocytosis and
bi- or multinucleation. The “koilocyte” (from the Greek “koilos” for “hollow’) is the classic
cytopathic manifestation of HPV infection in squamous epithelium, and is a squamous cell with a
prominent perinuclear cytoplasmic halo and a hyperchromatic, “raisin-like” nucleus.
The types of HPV associated with condyloma acuminatum are the low-risk types 6 and 11. They are
treated by local ablation – surgical removal, cryosurgery, electro-coagulation etc.
Gross photo of condylomata acuminata
Gross photo of condylomata acuminata 2
Malignant
These comprise squamous cell carcinoma, malignant melanoma, and basal cell carcinoma. In rare
instances, urethral carcinomas may extend to involve the vulva. Adenocarcinomas may arise from
skin adnexal structures or Bartholin's gland.
Squamous cell carcinoma
This may be in situ or invasive. The frequency of progression of in situ disease to invasive is
uncertain but has been estimated as 2% to 10%.
The term vulvar intraepithelial neoplasia (VIN) has now largely replaced other designations for
in situ squamous proliferations of the vulva:
VIN I (mild dysplasia) is diagnosed when the lower one-third of the epidermis is replaced by the
malignant squamous cells.
VIN II (moderate dysplasia) comprises malignant cells in the lower two-thirds of the epidermis.
VIN III (severe dysplasia/carcinoma in situ) comprises malignant cells in greater than two-thirds
(to the full thickness) of the epidermis.
Gross picture, VIN III
Features of HPV infection may be superimposed on VIN, particularly in younger women. Up to
about 30 years ago, VIN was usually found in women in the 5th and 6th decades, but currently,
about a half of the patients are less than 40 years old. This is thought to be due to the increasing
association with HPV infection.
Invasive squamous cell carcinoma accounts for greater than 90% of all vulvar malignancies.
Over 90% of the patients are post-menopausal and most are over the age of 60. The lesion usually
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begins on the labia majora, is slow growing and tends to grow in a destructive, infiltrating manner
often with ulceration. Inguinal (groin) lymph nodes are the commonest site for metastases.
Gross picture of squamous cell ca of vulva; Histology of invasive squamous cell ca of vulva
The lesions may be multifocal and may be associated with malignancies elsewhere in the genital
tract, especially the cervix.
There is a strong association with HPV infection and VIN changes may often be seen adjacent to
the frank carcinoma.
Treatment is usually surgical +/- radiotherapy, and prognosis is related to the presence or absence of
lymph node involvement; 5-year survival is 70-80% with negative nodes and 40-50% with positive
nodes.
Mortality increases with the number of lymph nodes involved by tumour, bilateral involvement of
groin nodes and metastases to pelvic lymph nodes.
Metastases to the vulva do occur, and are usually seen in advanced carcinoma of the genital tract,
most commonly of the cervix.
Paget's disease of the vulva usually presents as a scaly, erythematous lesion on the vulva and in
most cases represents a metastatic, intra-epidermal adenocarcinoma arising from an underlying
sweat gland carcinoma.
VAGINA
Pathologically, important benign vaginal lesions are uncommon. Perhaps the only one worth
mentioning (though uncommon) is vaginal adenosis - metaplastic foci of endocervical glandulartype epithelium in the normal squamous epithelium – sometimes related to in utero exposure to
diethylstilbestrol (DES). The natural history is that of slow self-healing, but there is said to be an
increased (albeit low) risk of clear cell adenocarcinoma in these patients.
Malignancies of the vagina include squamous cell carcinoma, adenocarcinoma,
rhabdomyosarcoma (sarcoma botryoides), malignant melanoma and metastatic carcinoma.
Squamous cell carcinoma comprises over 90% of vaginal malignancies. Most represent extension
from cervical cancers and true primary vaginal squamous cell carcinomas are rare.
Adenocarcinomas are most commonly found in older patients.
Rhabdomyosarcoma (sarcoma botryoides) is a rare malignancy of infants and children, and most
occur under 2 years of age. The lesion presents as polypoid masses resembling bunches of grapes
(hence the name). The prognosis used to be uniformly poor but has improved considerably with the
use of a combination of surgery and multi-agent chemotherapy.
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Metastatic carcinoma originates from genital and pelvic organs such as cervix, ovary,
endometrium, rectum and kidney.
CERVIX UTERI
The main diseases of the cervix uteri may be discussed under the following headings:
 Inflammation
 Polyps
 Carcinoma
Inflammation
Acute
Acute cervicitis may be caused by non-specific bacterial infection or may arise secondary to
specific sexually transmitted diseases e.g. gonorrhoea, herpes, trichomonas, chlamydia etc.
The pathological appearances are those of the standard acute inflammatory process as seen
elsewhere in the body.
Chronic
Chronic cervicitis is ubiquitous in older women and the severity varies considerably. Squamous
metaplasia of the endocervical epithelium (mucin-secreting columnar) often accompanies chronic
inflammation. The inflammatory process may lead to occlusion of the endocervical glands (these
are really crypts and not true glands) with retention of secretions, dilatation and formation of cysts
known as nabothian cysts (seen clinically as nabothian follicles).
Polyps
Endocervical polyps are really overgrown folds of endocervical mucosa. They often contain
cystically dilated glands in a vascular, fibrous stroma and may ulcerate and bleed. They are not
premalignant. Gross (clinical) endocervical polyp
Carcinoma
Cancer of the cervix is thought to begin in a single cell (or clone of cells) at the squamocolumnar
transformation zone (TZ).
Cervical cancer has two phases:
 Pre-invasive disease (Cervical Intraepithelial Neoplasia)
 Invasive disease.
Cervical Intraepithelial Neoplasia (CIN)
This term is now used to characterize “precancer” of the cervix and describes the aberrant changes
occurring in the cervical epithelium as it becomes neoplastic and is replaced by abnormal cells.
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These abnormal cells show loss of normal maturation, loss of polarity, excessive and abnormal
mitotic activity, increased nuclear-cytoplasmic ratio and nuclear hyperchromasia and
pleomorphism. The term dysplasia was used (and still is by some people) to describe these changes
in the past and cervical dysplasia is graded as follows:
 Mild dysplasia – the abnormal cells are predominantly confined to the lower third of the
epithelium
 Moderate dysplasia – the abnormal cells extend into the middle third of the epithelium
 Severe or marked dysplasia – the abnormal cells extend into the upper third of the epithelium
 In situ carcinoma – the full thickness of the epithelium is replaced by the abnormal cells.
Over the past 2 decades, this "dysplasia" classification of premalignant cervical disease fell from
favour because:
1) There was a tendency to treat different grades of dysplasia as separate entities rather than as
stages of a disease that may co-exist and convert from one to another.
2) Severe dysplasia and in situ carcinoma are difficult to separate objectively in histology sections
and behave biologically as one and the same entity.
The term cervical intraepithelial neoplasia (CIN) was introduced to encompass the whole
spectrum of premalignant change in the cervical epithelium, and its usage implies a unified concept
of a single disease process. CIN is divided into three grades:
 CIN I – lesions previously described as mild dysplasia
 CIN II – lesions previously described as moderate dysplasia
 CIN III – lesions previously classified as severe dysplasia or in situ carcinoma.
Subsequent to the CIN nomenclature, another classification system was introduced in the USA –
the Bethesda System – which uses only two grades of abnormality known as:
 LSIL – low-grade squamous intraepithelial lesion (corresponding to CIN I)
 HSIL – high-grade squamous intraepithelial lesion (corresponding to CIN II or CIN III).
Dysplasia
Mild
Moderate
Severe/Ca-in situ
CIN Bethesda
I
II
III
LSIL
HSIL
HSIL
The CIN concept seeks to underscore the fact that premalignant disease of the cervix is a continuum
and is neoplastic change that starts from one end of a spectrum and may progress to in situ
carcinoma. Most CIN lesions do NOT progress to invasive cancer, but all tend to be treated as
potential cancers as it is not possible to predict clinically or histologically which lesion will
progress.
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We do know, however, that the chances of progression depend heavily on the grade of CIN
– the higher the grade, the greater the probability of progression will be (see below under “HPVs”
for link to HPV type).
Figures vary, but it has been reported that spontaneous regression occurs in about
 60% of CIN I,
 40% of CIN II
 33% of CIN III lesions
Progression to CIN III occurs in about
 10% of CIN I
 20% of CIN II lesions.
The time taken for progression is not known and there is probably marked variation in individual
cases, but the progression time from CIN I to CIN III has been estimated to have a mean duration
of 12 to 15 years.
It is thought that only a small minority of CIN III lesions will progress to invasive cancer, usually in
the range of 1-5%.
Therefore, in any individual patient, any CINIII lesion has to be regarded as potentially invasive and
must be managed appropriately.
Aetiology and Epidemiology of Cervical Carcinoma
Epidemiological studies have demonstrated a positive association between squamous cell
carcinoma of the cervix and the following factors:
 Early age of first coitus
 Multiple sexual partners AND/OR a male partner with multiple previous sexual partners
 Multiparity
 Low socio-economic status
 Cigarette smoking
 A history of STD’s, especially genital warts
 Immunosuppression from any cause (including HIV infection)
It had always been clear that the epidemiological profile of cervical cancer fit that of a sexually
transmitted disease, and it had long been postulated that a carcinogen (or carcinogens) was
transmitted sexually from the man to the woman, a hypothesis made much more plausible when it
was also noted that there was a higher incidence of cervical cancer in women whose sexual partners
had a history of:
 Recurrent STD's and /or
 Poor genital hygiene and/or
 Carcinoma of the penis
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Over the years, various agents had been implicated as this carcinogenic factor, including
gonococcus, treponema pallidum, chlamydia and HSV, but none of these were satisfactorily
substantiated.
In the 1970s, a high prevalence of cervical HPV infection was noted in cytological and histological
samples of women with CIN and invasive cancer of the cervix, leading to HPV being implicated as
the sexually transmitted causative agent in CIN/cervical cancer.
HUMAN PAPILLOMA VIRUSES (HPVs)
These are DNA tumour viruses that predominantly affect skin and mucous membranes producing
characteristic epithelial proliferations at the sites of infection.
There are many serotypes, with most being relatively site-specific when they infect.
Those that frequent the genitals are known as ano-genital HPVs.
Most anogenital HPV infections are transient and self-limiting, and the majority of infected
women will clear the infection within two years.
HPVs are classified into two main types:
 “low-risk” – those not associated with cervical carcinoma
 “high-risk” – those associated with cervical carcinoma.
Low-risk types
These are typified by types 6 and 11, and are associated with “low-grade” lesions, i.e. CIN I (LSIL),
which may manifest themselves as condylomas, e.g. condylomata acuminata or flat condylomas.
When these HPVs infect the cervical epithelium, the viral DNA does not integrate into the genome
of the host cell, but exists as free extrachromosomal forms within the nucleus called “episomes”.
High-risk types
These are typified by types 16 and 18 and are associated with “high-grade” lesions, i.e. CIN II & III
(HSIL), and invasive carcinoma.
When these HPVs infect the cervical epithelium, the viral DNA integrates into the host genome and
viral DNA replicates independently of host DNA synthesis.
Viral DNA integration disrupts the HPV E2 gene which results in the loss of normal E2 downregulation of the E6 and E7 genes.
The E6 and E7 genes encode for proteins that:
a. Inactivate or block the host tumour suppressor genes p53 and RB1 in the host cells,
and
b. Activate cell cycle-related genes e.g. cyclin E, causing uncontrolled cellular
proliferation.
This combination [plus or minus a co-factor(s)] sets the stage for malignant transformation of the
cervical epithelium.
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In summary, the epidemiological studies now suggest the following natural history. When
women begin sexual intercourse in their teens or twenties, HPV infection is a common result.
Most women develop no clinical evidence of disease (latent infection) and eventually suppress
and lose the infection. Others get low-grade lesions (infection with low-risk HPVs) many of
which regress spontaneously (? via innate host defence mechanisms).
However, a minority of women develops persistent infection (? due to an inadequate immune
response) and if these infections are with high-risk HPV types then, perhaps with the facilitation
of genetic factors and other co-factors such as cigarette smoking, progression to high-grade CIN
may occur.
To put things in perspective however, please note that only about 3% to 4% of women
infected with HPV worldwide go on to develop cervical cancer.
Incidence and Prevalence
The Jamaican Cancer Registry, which documents malignancies in Kingston and St. Andrew, gives
the following statistics for carcinoma of the cervix and for breast cancer – the top two cancers in
Jamaican women (figures quoted as crude incidence rate per 100,000 women per annum):
Years
1978-1982
1983-1987
1988-1992
1993-1997
Breast
Cancer
28.6
32.2
36.0
35.0
Invasive Cervical
Cancer
20.5
21.5
21.9
21.0
In situ Cervical
Cancer
10.6
15.6
40.4
30.0
Total Cervix
Cancer
31.1
37.1
62.3
51.0
The incidence of breast cancer has been consistently higher than that of invasive cervical cancer.
The combined figure for cervix is not used as in situ cervical cancer is not biologically active, i.e. is
not locally destructive and does not metastasize. Note also that the overall incidence of invasive
cervical cancer has remained virtually unchanged.
Squamous Cell Carcinoma
The majority (approx. 90%) of cervical carcinomas are squamous cell carcinomas (SCC). Invasive
SCCs are classified as (1) Microinvasive or (2) Invasive (frankly).
Microinvasive
Microinvasive carcinoma (MICA) is an invasive carcinoma, i.e. the malignant cells have broken
through the basement membrane to invade the underlying stroma, but the neoplasm by definition is
deemed to be smaller than a “frankly” invasive carcinoma.
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There are two commonly used definitions of MICA.
1) The Society of Gynecological Oncologists (SGO) in the USA define MICA as an invasive
lesion with a depth of stromal invasion of 3 mm or less below the basement membrane of
the epithelium, in which there is no evidence of vascular invasion. The presence of
vascular invasion by tumour cells classifies the tumour as a frankly invasive carcinoma no
matter the depth of stromal penetration.
2) The International Federation of Gynecologists and Obstetricians (FIGO) define MICA
as an invasive lesion than invades to a depth of not more than 5 mm below the basement
membrane with a horizontal spread not exceeding 7 mm.
MICA, although being invasive,has a good prognosis that is just slightly worse than that of CIN III.
Invasive
Grossly, these may be polypoid (fungating), papillary, nodular or ulcerating, and histologically they
show varying degrees of differentiation. Local invasion (direct extension) involves the corpus uteri,
vagina, parametrium, bladder and rectum. Metastases are via lymphatics to pelvic, inguinal, iliac
and para-aortic lymph nodes. Haematogenous spread to liver, lungs and bone occurs, but at a very
late stage. Death is more often due to the effects of local invasion (ureters, bladder, rectum etc.)
rather than to metastases, and most deaths are due to uraemia secondary to ureteric obstruction.
Colposcopic picture of ca cervix
Clinical picture of ca cervix
Treatment and prognosis depends on the stage of the tumour. A simplified clinical staging system is
as follows:
 Stage 0:
Carcinoma in situ (CIN III)
 Stage I:
Carcinoma confined to the cervix
 Stage Ia:
Microinvasive carcinoma
 Stage 1b:
Invasive (frankly)
 Stage II:
Extension beyond the cervix into the upper two-thirds of the vagina
 Stage III:
Extension to the pelvic wall and/or lower third of the vagina
 Stage IV:
Extension beyond the pelvis or into urinary bladder or rectum
Treatment/Prognosis
The gynaecologists will cover this area comprehensively. The following is a mere synopsis.
 CIN is usually removed by any of a variety of methods including cryocautery, laser therapy,
loop diathermy or a cone biopsy. Patients are followed up by Pap smears and/or colposcopy
to exclude recurrence.
 Microinvasive carcinoma is usually treated by total hysterectomy.
 Other stage I tumours are treated by radical hysterectomy or radiotherapy.
 Stages II – IV are treated by radiotherapy.
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The 5-year survival for stage I carcinomas with negative lymph nodes is 90%, and this falls off
to about 70% for stage II, 30% for stage III and 10% for stage IV.
Cervical Screening By Cervical (Pap) Smears
Cytological screening for cervical cancer by the use of the Pap smear has revolutionized investigation of the disease. In 1928 Dr. George Papanicolaou, a pathologist, presented his findings that
cancer cells could be found in the vaginal fluid of women with cancer of the cervix. In the mid1940s, Dr. J. Ernest Ayre described the method we know today as the Pap smear when instead of
studying vaginal pool secretions like Papanicolaou, he used a spatula to directly scrape cells from
the cervix. Pap smear screening for cancer of the cervix became widespread by the 1950s, and in
countries where it has been used effectively it has dramatically reduced the number of deaths
from this disease because of early detection of CIN lesions.
A special wooden spatula (Ayre's spatula), or some similar device, is used to gently scrape
the superficial cells from the TZ and adjoining ectocervix. This material is smeared on a glass
slide, stained with the Papanicolaou stain and examined under the microscope for the cellular
features of CIN.
This photomicrograph shows numerous koilocytes on a pap smear indicative of HPV infection. The arrow points
to a binucleate koilocyte.
Abnormalities may be followed up by colposcopy. The colposcope is an instrument used by the
gynaecologist to examine the cervix grossly. It magnifies the cervix to an extent whereby
abnormal vascular and epithelial patterns characteristic of varying grades of CIN may be
diagnosed. These areas are then biopsied for histological confirmation.
Adenocarcinoma
These account for about 5-10% of cervical cancer. The risk factors are not as clearly defined as for
squamous cancer but a relatively strong association with HPV infection has been reported.
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They are adenocarcinomas of varying degrees of differentiation. Prognosis is related to the
stage of the lesion and tends to be worse than the corresponding stage for squamous cell carcinoma
because of the tendency for the lesion to spread to lymph nodes early.
Reference websites:

Pictures of various areas of gynaecological pathology:
http://www-medlib.med.utah.edu/WebPath/ORGAN.html, then click on “female genital
tract pathology”

Lectures on gynaecological pathology:
http://cats.med.uvm.edu/cats_teachingmod/pathology/path302/gyn/home/gynindex.html

Tumours of female reproductive organs:
http://www.bioscience.org/atlases/tumpath/freprod/freprod.htm
CTE/cte/Feb 2007